Cao et al. demonstrated that the LRRC8A/C volume-regulated anion channel (VRAC) transfers cGAMP from irradiated cancer cells into immune cells within the tumor, and enhances their effector function. TCR signaling opened VRAC pores to facilitate cGAMP import, leading to STING activation, interferon-α/β induction, and upregulation of granzymes and IFNγ in CD8+ T cells. ENPP1 and CD39 blockade maintained extracellular ATP and cGAMP levels. and further supported VRAC-mediated CD8+ T cell activation. Human TCGA analysis revealed that high LRRC8A/C correlated with enhanced STING signaling, T cell responses, and improved OS in various cancers.
Contributed by Shishir Pant
ABSTRACT: The volume-regulated anion channels (VRACs) transport osmolytes, neurotransmitters, and cyclic GMP-AMP (cGAMP) across the cell membrane to regulate cell volume and host defense. We report that the leucine-rich repeat-containing 8A/C (LRRC8A/C) VRAC plays a crucial role in immune responses to radiotherapy and chemotherapy for cancer. VRACs transfer cGAMP from irradiated cancer cells to infiltrating CD4 and CD8 T cells, thus enhancing their effector functions. TCR signaling acts as a physiological signal to open the VRAC pore through phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] and reactive oxygen species (ROS). This allows the rapid uptake of cGAMP and STING activation in mouse and human T cells and induction of interferon-α/β, which up-regulate granzymes and IFN-γ in CD8 T cells. Inhibition of the extracellular hydroxylases CD39 and ENPP1 maintains extracellular ATP and cGAMP, which promotes VRAC-enhanced CD8 T cell anticancer function. Thus, the transfer of cGAMP to T cells by VRACs may be a strategy that can be targeted in future cancer therapies.
Author Info: (1) State Key Laboratory of Immune Response and Immunotherapy, Shanghai Institute of Immunity and Infection, University of Chinese Academy of Sciences, Chinese Academy of Sciences,
Author Info: (1) State Key Laboratory of Immune Response and Immunotherapy, Shanghai Institute of Immunity and Infection, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China. (2) State Key Laboratory of Immune Response and Immunotherapy, Shanghai Institute of Immunity and Infection, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China. Clinical Translational Research Center, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200092, China. (3) State Key Laboratory of New Drug and Pharmaceutical Process, Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, Shanghai 200437, China. (4) Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. (5) State Key Laboratory of Immune Response and Immunotherapy, Shanghai Institute of Immunity and Infection, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China. (6) Center for Allergic and Inflammatory Diseases and Department of Otolaryngology, Head and Neck Surgery, Affiliated Eye, Ear, Nose and Throat Hospital, Fudan University, Shanghai 200031, China. CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China. (7) State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou 730000, China. (8) State Key Laboratory of Immune Response and Immunotherapy, Shanghai Institute of Immunity and Infection, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China. (9) State Key Laboratory of Immune Response and Immunotherapy, Shanghai Institute of Immunity and Infection, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China. Key Laboratory of Infection and Immunity of Shandong Province and Department of Immunology, School of Biomedical Sciences, Shandong University, Jinan 250012, Shandong, China. (10) State Key Laboratory of Immune Response and Immunotherapy, Shanghai Institute of Immunity and Infection, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China. (11) Center for Allergic and Inflammatory Diseases and Department of Otolaryngology, Head and Neck Surgery, Affiliated Eye, Ear, Nose and Throat Hospital, Fudan University, Shanghai 200031, China. (12) Center for Allergic and Inflammatory Diseases and Department of Otolaryngology, Head and Neck Surgery, Affiliated Eye, Ear, Nose and Throat Hospital, Fudan University, Shanghai 200031, China. (13) School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China. (14) Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. (15) CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China. (16) State Key Laboratory of Immune Response and Immunotherapy, Shanghai Institute of Immunity and Infection, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China. (17) State Key Laboratory of Immune Response and Immunotherapy, Shanghai Institute of Immunity and Infection, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China. (18) State Key Laboratory of Immune Response and Immunotherapy, Shanghai Institute of Immunity and Infection, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China. (19) Suzhou Blood Center, Suzhou 215000, Jiangsu, China. (20) Suzhou Blood Center, Suzhou 215000, Jiangsu, China. (21) State Key Laboratory of Immune Response and Immunotherapy, Shanghai Institute of Immunity and Infection, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China. (22) CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China. (23) CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China. (24) State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China. (25) Shenzhen Medical Academy of Research and Translation, Shenzhen 518107, Guangdong, China. (26) Key Laboratory of Infection and Immunity of Shandong Province and Department of Immunology, School of Biomedical Sciences, Shandong University, Jinan 250012, Shandong, China. (27) State Key Laboratory of Immune Response and Immunotherapy, Shanghai Institute of Immunity and Infection, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China. (28) State Key Laboratory of New Drug and Pharmaceutical Process, Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, Shanghai 200437, China. (29) Departments of Physiology, Neuroscience, and Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. (30) School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China. (31) School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China. (32) Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. (33) Clinical Translational Research Center, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200092, China. (34) Center for Allergic and Inflammatory Diseases and Department of Otolaryngology, Head and Neck Surgery, Affiliated Eye, Ear, Nose and Throat Hospital, Fudan University, Shanghai 200031, China. (35) State Key Laboratory of Immune Response and Immunotherapy, Shanghai Institute of Immunity and Infection, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
